14beta, 21-epoxy-pregnanes and method of preparing the same



United States Patent I O 3,146,230 145,21-EPOXY-PREGNANES AND METHOD OFPREPARING THE SAME 1 Francis J. McEvoy, Pearl River, and Milton D.Heller and Seymour Bernstein, New City, N.Y., assignors to AmericanCyanamid Company, Stamford, Conn., 21 corporation of Maine No Drawing.Filed Aug. 28, 1962, Ser. No. 220,034 14 Claims. (Cl. 260-23955) Thisinvention relates to new pregnanes. More particularly, it relates to145,21-ep'oxy pregnanes, intermediates and methods of preparing thesame.

The novel steroids of the present invention can be, in

general, illustrated by the following formula:

'CHa

cgczcs wherein C is a member of the group consisting of +=O, H(:J(fl) OHand lower alkanoyl-0 (13) (:JH

C C is a member of the group consisting of X is a divalent radical ofthe group consisting of O-CHz-C- NO CH radicals and when C is (15H(fl)-O-lower alkanoyl then X is selected from the group consisting ofo-cH,-0- and O-CHz-(fll- NO CH1 0 radicals.

The compounds of the present invention are, in general, crystallinesolids substantially insoluble in Water andyloxy-ZO-methoxyirnino-14fl-pregnan-14/3-ol (II). When compound (II) isheated with an alcoholic alkali metal hydroxide the product obtained is2O-methoXyimino-14 S, 2l-epoxy-l4fl-pregnan-3fi-ol (III). Heating thelatter steroid under acidic conditions in a solvent produces 3,3-hydroxy-14B,2l-epoxy-14B-pregnan-20-one (IVA). Acetylating the lattercompound produces 3,B-acetoxy-14fi,21- epoxy-14fl-pregnan-20-one (IVB).The steroid (IVA) when reacted With chromic acid in the presence ofsulfuric acid produces 1413,21-epoxy-14fl-pregnane 3,20 dione (V). Thelatter compound when treated with bromine and hydrogen bromide produces4-bromo-14;3,21-epoxy- 14,8-pregnane-3,20-dione (VI). The latter steroidon heating with lithium chloride in the presence of a solvent producesl4fl,2l-epoxy-14fi-pregn-4-ene-3,20-dione (VII). When the steroid 33-hydroxy-14fl,21-epoxy-14B-pregnan- 20-one (IVA) is reacted withchromic acid in acetic acid the product obtained is 148-hydroxy-3,20-diketo-14,8- pregnan-Zl-oic acid 21,14-lactone (VIII).The latter steroid on contacting with bromine in the presence of aceticacid produces 4-bromo-14fi=hydroxy-3,20-diketo- 14fl-pregnan-21-oic acid21,14-1actone' (IX). The latter on heating with lithium chloride in thepresence of dimethylformamide produces l4p-hydroxy- 3,20-diket0-14,8-pregn-4-en-2l-oic acid 21,14-lactone (X). The preparation of the variouscompounds described above isshown in the following flowsheet.

cno fi C=O 0 0 ca3 CH3 on c 8 (VIII) 0 H (VI) 0 6:0 0 c=o on. CH

o H (Ix) (v11) The present compounds have been found to possess diureticactivity. They are, therefore, useful in the treatment of edema andelimination of fluid in the tissues in conditions such as ascites, andcardiac malfunctions.

The following examples illustrate in detail the preparation ofrepresentative compounds of the present invention.

EXAMPLE 1 Preparation of 35-11 cetoxy-Z O-Methoxyimino-Mfi-Pregnan-14fi,21-Diol (I) To a solution of 300 mg. of3fi-acetoxy-l4fi,21-dihydroxy-l4B-pregnan-20-one and 300 mg. ofmethoxyamine hydrochloride in 45 ml. of methanol is added a solution of600 mg. of potassium acetate in 6 ml. of water. The solution is refluxedfor 18 hours and then diluted with 30 ml. of water. The aqueous solutionis extracted with ethyl acetate. Evaporation of the organic extractyields the product, v 3380, 1734, 1710 (shoulder) 1252, 1230 cm.-

EXAMPLE 2 Preparation of 3fi-Acet0xy-21-Methanesalfonyl0xy20-Methoxyimino-Mfi-Pregnan-l4ti-Ol (II) A solution of 290 mg. of3B-acetoxy-20-methoxyimino- 14fl-pregnane-14fi,2l-diol in ml. ofpyridine is cooled to 32 C., and 0.27 ml. of methanesulfonyl chloride isadded. The solution is maintained at 5 C. for 22 hours. The product isprecipitated by the addition of water. Recrystallization fromacetone-petroleum ether gives melting point 149-150 C., dec.

EXAMPLE 3 Preparation of Z0-Meth0xyimin0-14B,21-Ep0xy-14,8-Pregnan-3B-Ol (Ill) To a suspension of 710 mg. of3fl-acetoxy-21-methanesulfonyloxy-20-methoxyimino-l4fl-pregnan-l4 8-olin 71 ml. of methanol is added 10.4 ml. of 3% methanolic potassiumhydroxide. The mixture is refluxed for 3 hours and the product isisolated by the addition of water; u 3450, 1052, 1032, 1082, 1092 GEL-1.

4 EXAMPLE 4 Preparation of 3fi-Hydroxy-14B,21 -Ep0xy-14,3-Pregnan-20-One (I VA A solution of 2.5 g. of20-methoxyimino-14t-3,2l-epoxy- 14fl-pregnan-3 8-ol in 250 ml. ofmethanol and 10 ml. of acetone and 250 ml. of 2 N hydrochloric acid isrefluxed for 4 hours. Concentration of the solution produced 1.62 g. ofproduct. Recrystallization from acetone-Water gives melting point 194197C.

EXAMPLE 5 Preparation of 3B-Acet0xy-14B,2I-Ep0xy- 14/3-Pregnan-20-One (1VB) To a solution of 800 mg. of 3B-hydroxy-14B,21-epoxy-14,8-pregnan-20-one in ml. of pyridine is added 0.61 ml. of aceticanhydride and the mixture is allowed to stand for 18 hours at roomtemperature. Water is added and the 750 mg. of product is collected.Recrystallization from acetone-Water gives melting point 134 C.

EXAMPLE 6 Preparation of 14,6,21-Ep0xy-14B-Pregnane- 3,20-Di0ne (V) To asolution of 100 mg. of 3B-hydroxy-14fi,21-epoxy- 14fl-pregnan-20-one in35 ml. of acetone, cooled to 5 C. is added a solution of 29.4 mg. ofchromic acid and 0.025 ml. of sulfuric acid in 0.11 ml. of water. Themixture is stirred for 5 minutes, then diluted with 175 ml. of water.The product is collected as a white solid. Recrystallization fromacetone-water gives melting point 238-239 C.

EXAMPLE 7 Preparation of 4-Br0m0-14B,21-Epoxy 14,8-Pregnane-3,2 O-DioneVI A solution of 330 mg. of 145,21-epoxy-14 8-pregnane- 3,20-dione in4.5 ml. of methylene chloride, 4.5 ml. of chloroform and 1.13 ml. ofacetic acid is cooled to -40 C. To the mixture is added dropwise asolution of 0.052 ml. of bromine in 0.245 ml. of 30% hydrogen bromide inacetic acid and 0.75 ml. of acetic acid. The addition takes 40 minutesand the solution is stirred an additional 30 minutes. A solution of 164mg. of anhydrous sodium acetate in 1.4 ml. of water is added and themixture is stirred at room temperature for 30 minutes. The organicsolvents are removed under reduced pressure and the addition of 19 ml.of water precipitates the product. Recrystallization from acetone-watergives melting point 191-192 C.

EXAMPLE 8 Preparation of 1 4 3,21 -Ep0xy-14fi-Pregn- 4-Ene-3,20-Di0ne(VII) A mixture of mg. of 4-bromo-145,21-epoxy-14/9- pregnane-3,20-dioneand 330 mg. of lithium chloride in 5 ml. of dimethylformamide is heatedat 100-110 C. in a nitrogen atmosphere for 3 hours. The solution iscooled, diluted with methylene chloride and washed' with sodiumbicarbonate solution. The organic solution is dried with magnesiumsulfate and the solvent is evaporated under reduced pressure leaving awhite solid. The solid is dissolved in methylene chloride andchromatographed on a synthetic magnesium silicate column. Elution withacetone-methylene chloride (1:50) gives the desired product.Recrystallization from acetone-water gives melting point 193-195 C.,

EXAMPLE 9 Preparation of 14 3-Hydr0xy-3,20-Diket0-14fl- Pregnan-Zl-OicAcid 21,14-Lactone (VIII) To a solution of 250 mg. of3B-hydroxy-14;8,2l-epoxy- 14,8-pregnan-20-one in 10 ml. of acetic acidis added a EXAMPLE Preparation of 4-Br0m0-14,8-Hydr0xy-3,Z0-Diket0-14;3-Pregnan-ZI-Oic Acid 21,14-Lact0ne (IX) To a solution of 490 mg. of14/3-hydroxy-3,20-diketo- 14B-pregnan-21-oic acid 21,14-1actone in 32ml. of acetic acid is added a solution of 0.073 ml. of bromine in 8 ml.of acetic acid. Water is added and the product is collected.Recrystallization from acetone-water gives melting point 197 C., dec.

EXAMPLE ll Preparation of 14f3-Hydroxy-3,20-Diket0-14/3-Pregn-4-en-ZI-Oic Acid 21,14-Lact0ne (X) EXAMPLE 12 Preparation of14,3-Hydr0xy-3,20-Diketo-J4,8-Pregn-4-en- 21 -Oic Acid 21,14-Lact0ne (X)To a solution of 84 mg. of 145,21-epoxy-14,8-pregn-4- ene-3,20-dione in3 ml. of acetic acid is added a solution of 84 mg. of chromic acid in 0.8 ml. of 90% aqueous acetic acid. The mixture is allowed to stand atroom temperature for 18 hours, then diluted with methanol and water. Themixture is extracted with ethyl acetate and the product is obtained byevaporation of the organic extract. Recrystallization from acetone-watergives melting point 259-261 C.

We claim:

1. A steroid of the formula:

wherein C is a member of the group consisting of 6 -C C is a member ofthe group consisting of Bromine X is a divalent radical of the groupconsisting of OCH -C 0OH2O and -OCC NOCHa H (H) g and when C is 4'! H(5) 0-lower alkanoyl then X is selected from the group consisting ofOCH5C and OOH3C NOOH3 i 2. The compound3,8-hydroxy-14,6,21-epoxy-14fi-pregnan-ZO-one.

3. The compound 3,8-acetoxy-l4/3,2l-epoxy-14B-pregnan-'ZO-one.

4. The compound 14,3,21-epoxy-14,8-pregnane-3,20-dione.

5. The compound -hydroxy-3,20-diketo-14fl-pregnan-Zl-oic acid21,14-lactone.

6. The compound 4-bromo-14{3-hydroxy-3,20-diketol4fi-pregnan-21-oic acid21,14-lactone.

7. The compound 14fl-hydr0xy-3,2-0 diket0-14fl-pregn- 4-en-21-oic acid21,14-lactone.

8. The compound 3B-acetoxy-ZO-methoxyimino-14[3 pregnan-l4,8,21-dio1.

9. The compound Bfi-acetoxy-Zl-methanesulfonyloxy-20-methoxyimino-14fi-pregnan-14,8-01.

10. The compound ZO-methoxyimino-145,21-epoxy- 14,3-pregnan-3B-ol.

11. The compound 4-bromo-14p,21-epoxy-14ii-pregnane-3,20dione.

12. The compound 14,8,21-epoxy-14 3-pregn-4-ene-3,20- dione.

13. A method of preparing 20-methoxyimino-14B,2lepoxy-145-pregnan-35-olwhich comprises heating 3!?- loweralkanoyloxy-Z1-methanesulfonyl-ZO-methoxyimino- 1413-pregnan-l4fl-ol ina lower alkyl alcoholic solvent in the presence of an alkali metalhydroxide.

14. A method of preparing 20-methoxyimino-l4fl,21- epoxy-14fl-pregnan-33-ol which comprises contacting 35- lower alkanoylZO-methoxyimino-14fl-pregnane-14fl,2ldiol with methanesulfonyl chloridein the presence of a solvent, heating the resulting reaction product ina lower alkyl alcohol in the presence of an alkali metal hydroxide andrecovering said product therefrom.

References Cited in the file of this patent Tschesche: AngewandteChemie, vol. 73, No. 2, 1961, pp. 727-735.

Ragab et al.: Helvetica Chimica Acta, vol. XLV, Feb. 1, 1962, pp.152-170.

Bernoulli et al.: Helvetica Chimica Acta, vol. XLV, Feb. 1, 1962, pp.240-251.

1. A STEROID OF THE FORMULA: